Selective Muscarinic Receptor Agonists

(KarXT)

Brain / Nervous System

TRIAL PHASE
MECHANISMINDICATION(S)PRODUCT NAMEPreclinicalPhase 1Phase 2Phase 3
Selective Muscarinic Receptor Agonists
Schizophrenia, Alzheimer’s Disease, Bipolar Disorder
Karuna
(KarXT)

Brain / Nervous System

Selective Muscarinic Receptor Agonists
INDICATION(S):Schizophrenia, Alzheimer’s Disease, Bipolar Disorder
NAME:Karuna (KarXT)
STAGE:Phase 1
Untapped neurotransmitter systems

Our affiliate Karuna is advancing a selective muscarinic receptor agonist program for the treatment of psychosis and cognition across multiple central nervous system (CNS) disorders including schizophrenia and Alzheimer’s disease. KarXT (Karuna-Xanomeline-Trospium), our lead product candidate, selectively targets M1/M4 muscarinic receptors in the brain while blocking their activation in peripheral tissues to significantly improve the tolerability profile. This approach is designed to unlock the therapeutic potential of muscarinic receptors, which have long been of interest to the pharmaceutical industry based on previous efficacy data in placebo-controlled human studies but have previously been held back by tolerability concerns associated with the activation of muscarinic receptors in peripheral tissues.

  • Patient Need & Market Potential
    • Psychosis and cognitive impairments are debilitating features of schizophrenia and Alzheimer’s disease and other mental illnesses that affect tens of millions of people, but there are no existing medicines that sufficiently and safely treat psychosis and cognition impairments.
    • Antipsychotics are the mainstay therapy; however, drugs currently in use all rely on the same fundamental mechanism of action and, despite widespread use, the prognosis for patients remains poor – only 30 percent live independently, 10-20 percent maintain full time employment, and tragically 5 percent end their life with suicide.
    • Current antipsychotics only address positive symptoms, but patients often experience residual positive symptoms throughout their lives; negative and cognitive symptoms are left untreated. There are no approved treatments for the negative or cognitive symptoms of schizophrenia, or the treatment of psychosis associated with Alzheimer’s disease.
    • Current antipsychotics are associated with serious side effects, including potentially irreversible movement disorders (tardive dyskinesia), metabolic dysfunction, glucose intolerance, weight gain, sedation, and cardiovascular mortality in the elderly.
    • There is a desperate need for new treatments in schizophrenia that not only address the positive, negative, and cognitive symptoms but are free of the problematic safety issues with existing medicines.
  • Our Approach to Solving the Problem
    • Xanomeline, a muscarinic agonist that we exclusively licensed, was previously studied (by Eli Lilly & Co) in double-blind, placebo-controlled trials in schizophrenia and Alzheimer’s disease, demonstrating efficacy in the treatment of psychosis and beneficial effects on cognition. To our knowledge, xanomeline is the only muscarinic agonist that has demonstrated human efficacy in either schizophrenia or Alzheimer's disease.
    • Eli Lilly discontinued development of xanomeline given tolerability issues associated with the activation of peripheral muscarinic receptors (but did not observe the serious side effects associated with the current anti-psychotics).
    • By pairing xanomeline with trospium chloride, a muscarinic antagonist that acts only in the periphery (outside the brain or CNS) and has been approved in the US and Europe for the treatment of overactive bladder, we believe KarXT could potentially alleviate the tolerability issues seen with xanomeline alone while maintaining the excellent efficacy profile previously demonstrated. In our tolerability proof-of-concept study, KarXT was significantly better tolerated than xanomeline alone and no serious or severe adverse events were reported.
  • Intellectual Property
    • We have broad intellectual property coverage worldwide, including exclusive rights to five patent applications which cover pharmaceutical compositions of its clinical candidate and methods of use for the treatment of disorders ameliorated by muscarinic receptor activation.
  • Team
    • We have assembled a seasoned team with strong expertise in neuroscience drug research and development 
    • Key advisors include Dr. Edmund Harrigan, who previously served as Senior Vice President of Worldwide Safety and Regulatory for Pfizer; Dr. Bennett Shapiro, previously the Executive Vice President of Research for Merck; Dr. Alan Breier, currently Professor of Psychiatry and Vice Chair for Clinical Research at Indiana University School of Medicine and Chief of the Psychotic Disorders Program; and Dr. Atul Pande, the former Senior Vice President, Head of Neuroscience, and Senior Advisor, Pharmaceutical R&D at GlaxoSmithKline.  
    • Karuna was developed and is being run by Dr. Andrew Miller, with Dr. Stephen Brannan 
  • Milestone Achieved
    • In December 2016, we announced positive results from a tolerability proof-of-concept study in which KarXT was shown to significantly reduce the incidence of prespecified cholinergic adverse events by a clinically meaningful extent (46 percent, p=0.016) compared to xanomeline alone, and each individual cholinergic adverse event was reported at a lower rate in the KarXT treatment arm; furthermore, no severe or serious adverse events were reported
    • In a double-blind, placebo-controlled monotherapy trial in schizophrenia patients, xanomeline showed a significant (p<0.05) 24-point reduction over placebo on the Positive and Negative Syndrome Scale (PANSS).
    • Xanomeline has been dosed in over 800 patients and has demonstrated efficacy in reducing psychosis and shown beneficial effects on cognition in placebo-controlled human trials in both Alzheimer’s disease and schizophrenia.
  • Collaborations
    • We licensed xanomeline from Eli Lilly, and Company advisors include the former Chief Medical Officer and former Executive Vice President of Research and Development from Eli Lilly.
    • We received the Wellcome Trust’s Translation Fund Award, consisting of an unsecured convertible note of up to $3.84 million from the Wellcome Trust for the combination tolerability proof-of-concept study.
  • Expected Milestones and Timing
    • We expect to initiate a Phase 2 trial of KarXT in the third quarter of 2018, with the goal of replicating existing efficacy data with xanomeline in patients with schizophrenia while alleviating tolerability issues.

This novel product candidate has the potential to be one of the most promising new mechanisms for the treatment of people with psychosis and cognitive impairments in serious CNS disorders that affect tens of millions of people.

If successful, KarXT could provide a new mechanism for treating schizophrenia, a field in which treatments have relied on the same fundamental mechanisms for the last half-century.

In December 2016, we reported positive results from our tolerability proof-of-concept study and are currently conducting a Phase 1 study using a proprietary co-formulation of xanomeline and trospium. A Phase 2 trial to evaluate the efficacy and safety of KarXT in people with schizophrenia is expected to begin in the third quarter of 2018.


 Core Proprietary Technology

Previous Studies with Xanomeline

Phase II Study of Xanomeline in Alzheimer’s Disease


Proof of Concept Study of Xanomeline in Schizophrenia



Selective Muscarinic Receptor Agonists Tolerability Proof of Concept Study

Study Design Highlights


Data & Key Findings